Abstract
Development of antimicrobial peptides (AMPs) as highly effective and selective anticancer agents would represent great progress in cancer treatment. Here we show that myristoyl-CM4, a new synthetic analog generated by N-myristoylation of AMPs CM4, had anticancer activity against MCF-7, MDA-MB-231, MX-1 breast cancer cells (IC50 of 3–6 μM) and MDA-MB-231 xenograft tumors. The improved activity was attributed to the effect of myristoyl on the cell membrane. Flow cytometry and confocal laser scanning microscopy results showed that N-myristoylation significantly increased the membrane affinity toward breast cancer cells and also effectively mediated cellular entry. Despite increasing cytotoxicity against HEK293 and NIH3T3 cells and erythrocytes associated with its anticancer activity, myristoyl-CM4 maintained a certain selectivity toward breast cancer cells. Accordingly, the membrane affinity toward breast cancer cells was two to threefold higher than that of normal cells. Glycosylation analysis showed that sialic acid-containing oligosaccharides (including O-mucin and gangliosides) were important targets for myristoyl-CM4 binding to breast cancer cells. After internalization, co-localization analysis revealed that myristoyl-CM4 targeted mitochondria and induced mitochondrial dysfunction, including alterations in mitochondrial transmembrane potential, reactive oxygen species (ROS) generation and cytochrome c release. Activation of caspase 9, caspase 3 and cleavage of PARP were observed in MX-1, MCF-7, and MDA-MB-231 cells after myristoyl-CM4 treatment. The current work indicates that increasing hydrophobicity by myristoylation to modulate peptide-membrane interactions and then target mitochondria is a good strategy to develop AMPs as anticancer agents in the future.
Highlights
Cancer is a major public health problem worldwide and the global cancer death will rise to more than 13 million by 2030
At 40 μM, FITC-CM4 fluorescence was observed on the surface of HEK-293 cells, whereas no fluorescence was observed in the cytoplasm. These results indicated that N-myristoylation of CM4 increased the membrane affinity in both breast cancer cells and normal cells, and the affinity to breast cancer cells was higher than to normal cells
Our study provides the first evidence of the anticancer effect of N-myristoylation of Antimicrobial peptides (AMPs) CM4, which exhibited excellent anticancer activity in MX-1, MDA-MB-231, and MCF-7 breast cancer cells (IC50 of 3–6 μM)
Summary
Cancer is a major public health problem worldwide and the global cancer death will rise to more than 13 million by 2030. In the United States, statistical data from 2017 show that 1,735,350 new cancer cases and 609,640 cancer deaths are projected to occur (Siegel et al, 2018). Breast cancer is the most common cancer and the primary cause of mortality in female around the world (Akram et al, 2017). Insufficient selectivity and targeting of healthy mammalian cells with many deleterious effects, as well as the development of resistance remain a serious challenge, especially in triple negative patients (Tobin et al, 2015). The development of new effective anticancer drugs with low toxicity to normal host cells would represent great progress in the treatment of cancers including breast cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
